The psychotropic drugs are widely utilized in the treatment of schizophrenia and schizoaffective disorder. The psychotropic drugs olanzapine (Zyprexa®, Eli Lilly & Co.), risperidone (Risperdal®, Janssen, Johnson & Johnson), quetiapine (Seroquel®, Astra Zeneca) and clozapine (Clozaril®, Novartis) accounted for $5 billion in worldwide sales in 2000. While approximately 50% of prescriptions for these drugs are written for schizophrenia, other indications are becoming increasingly important, including bipolar disorder and depression, which each represent about 15% of prescriptions, and obsessive compulsive and anxiety disorders which are also beginning to be treated with these drugs.
Among psychotropic drugs, olanzapine and clozapine have been observed to induce weight gain, diabetes and other metabolic derangements in 50% of treated patients. The most serious medical side effect is the progression to Diabetes and Metabolic Syndromes (DIMS). These metabolic syndromes are diagnosed by the combination of abdominal obesity, atherogenic dyslipidemia, high fasting glucose, and elevated blood pressure. Specifically, DIMS is characterized by the following abnormalities occurring individually or in combination: (1) large waist circumference (>102 cm in men, 88 cm in women), (2) elevated serum triglycerides (>150 mg/dL), (3) depressed high density lipoprotein (HDL, <40 mg/dL in men, 50 mg/dL in women), (4) elevated blood pressure (systolic >130 mm Hg or diastolic ≧80 mmHg), and (5) elevated serum glucose (>110 mg/dL). The medical community is just now beginning to appreciate how disabling and burdensome DIMS can be to patients already suffering from psychiatric disease. The specter of obesity and DIMS could reduce compliance with psychotropic drugs and lead to low self-esteem and social withdrawal in already marginalized patients. Further, obesity and diabetes introduce serious medical complications (e.g. vascular disease, neuropathy), which increase the need to avoid the progression to metabolic syndromes in the first place. Hence, judicious selection of psychotropic therapeutic strategies to improve symptoms must be balanced with the expense of equally detrimental drug side effects. The need for “double prevention,” i.e., prevention of schizophrenia by early psychiatric management with psychotropic drugs and prevention of drug side effects by early medical management of the metabolic side effects, is therefore apparent.
The development of hyperglycemia and other metabolic syndromes cannot be explained solely on grounds of action of psychotropic drugs on the central nervous system and satiety for two principle reasons. First, other antagonists of serotonin, histamine, or adrenergic receptors, whether alone or in combination, do not provoke DIMS. Second, a high proportion of HIV-infected patients receiving protease inhibitors as part of the “Highly Active Anti-Retroviral Therapy” (HAART) regimen also develop DIMS (Fantoni, et al. 2003, AIDS 17 Suppl 1, S162). In contrast to psychotropic drugs, protease inhibitors do not influence appetite or satiety. It is therefore likely that unknown or unexpected pathways coalesce into DIMS.
The medical community would benefit from screening methods which identify individuals at risk of developing DIMS. The emerging field of physiogenomics offers an important approach for integrating genotype, phenotype, and population analysis of functional variability among individuals. In physiogenomics, genetic markers (e.g. single nucleotide polymorphisms or “SNPs”) are analyzed to discover statistical associations to physiological characteristics or outcomes in populations of individuals. Physiogenomics allows screening hundreds of candidate genes and physiological measurements of psychiatric disorders and metabolic syndromes, to explore an extensive variety of hypothetical pathways that might be involved in the development of psychotropic drug DIMS.
It is therefore an object of the present invention to provide physiogenomic methods for identifying individuals at risk of developing DIMS or other metabolic side effects associated with the class of psychotropic drugs or associated with specific psychotropic drugs.